Angiogenesis is a complex cellular process involving the branching, expansion, and maturation of primordial blood vessels into a complex microvasculature. The Angiopoietin/Tie receptor-ligand system plays a central role in these events. The Angiopoietins are secreted molecules that signal through the endothelial specific Tie2 receptor. This is a unique receptor tyrosine kinase signaling system in that distinct Angiopoietin ligands, although highly homologous, may function as agonist or antagonist in a context dependent manner. A detailed understanding of the mechanisms of Angiopoietin-Tie signaling and their function during angiogenesis requires comprehensive structural and biophysical analysis of both the Angiopoietins and the Tie receptors as well as of their interactions. The specific goals of this proposal include: i) structural analysis of the ligand binding domain of at least two Angiopoietin family members, ii) structural analysis of the ligand-binding domain of Tie2 as well as of the equivalent region of the related orphan receptor Tie1, iii) structural analysis of receptor recognition and formation of an Angiopoietin-Tie2 complex and iv) biochemical characterization of Angiopoietin-Tie interactions and receptor activation. [unreadable] [unreadable]